Process for the preparation of 2-aminomethylpyridine derivative

ABSTRACT

Process for the preparation of 2-aminomethylpyridine derivative of general formula (I) or a salt thereof, formula (I) in which:—n represents 0, 1, 2 or 3,—X is halogen atom,—each Y may be the same or different and may be a halogen atom, a halogenoalkyl, an alkoxycarbonyl or an alkylsulphonyl.

CROSS REFERENCE TO RELATED APPLICATION(S)

The present application is a 35 U.S.C. §371 national phase conversion ofInternational Application No. PCT/EP2003/014892 filed Nov. 18, 2003,which claims priority of European Patent Application No. 02356236.6filed Nov. 20, 2002.

The present invention relates to a novel process for the preparation of2-aminomethylpyridine derivatives which are useful as intermediates forthe preparation of pesticides, by catalytic hydrogenation of2-cyanopyridine derivatives.

Certain catalytic hydrogenation reactions of cyanopyridines to obtainaminomethylpyridines have been disclosed. An additional difficultyexists when the cyanopyridine is substituted by an halogen atom, due todehalogenation competitive reaction that can take place, as stated in P.N. Rylander, Hydrogenation Methods (Best Synthetic Series, published byAcademic Press), (1985), page 148.

Patent application EP0409716 discloses the use of Raney nickelassociated with a catalyst inhibitor in the presence of iodide. Thisprocess presents the drawback in that it uses a catalyst inhibitor. Suchan inhibitor should be avoided on an industrial scale.

Patent application WO 02/16322 discloses the use of a metal catalyst(especially palladium) in an alcohol solvent to carry out this reaction.Nevertheless, this process suffers from the disadvantage ofdehalogenation reaction due to the high activity of palladium.Furthermore, palladium is a catalyst which is very expensive and whichis very sensitive to catalysts poisons, such as the sulfur compoundswhich are formed during the process leading to the production of2-cyanopyridines. This hydrogenation process can not be used on anindustrial scale.

We have now found a process to prepare 2-aminomethylpyridine derivativewhich does not possess the above mentioned drawbacks and which isapplicable to industrial scale process.

Accordingly, the present invention relates to a process for thepreparation of 2-aminomethylpyridine derivative of general formula (I)or a salt thereof:

in which: n represents 0, 1, 2 or 3,

-   -   X is halogen atom,    -   Y may be the same or different and may be a halogen atom, a        halogenoalkyl, an alkoxycarbonyl or an alkylsulphonyl;

by hydrogenation of a 2-cyanopyridine derivative of general formula (II)or a salt thereof:

in which n, X and Y are as defined above, in acetic acid using Raneynickel, at a temperature of from 30° C. to 70° C., under a hydrogenpressure of from 1 to 50 bar.

For the purposes of the present invention:

halogenoalkyl means C₁-C₆ alkyl moiety substituted by one or morehalogen atoms;

alkoxycarbonyl means C₁-C₆ alkoxycarbonyl. Suitable examples of such amoiety may be methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl andi-propoxycarbonyl; alkylsulphonyl means C₁-C₆ alkysulphonyl;

a halogen atom may be a bromine atom, a chlorine atom, a iodine atom ora fluorine atom.

In the following description Raney nickel will be referred as to Ni—Ra.

The product obtained by the process according to the present inventionis the acetate of the compound of general formula (I) which is fullysoluble in acetic acid. The catalyst may then be recycled by filtrationand the solution of the acetate of the compound of general formula (I)is assayed according to methods well-known by the man ordinary skilledin the art. Yield of acetate of the compound of general formula (I) withrespect to 2-cyanopyridine derivative of general formula (II) is usuallymore than 95%. At 45° C., even with Ni—Ra damp with water, no more than0.1% yield of dehalogenation product is generally observed in theabsence of dehalogenation inhibitors such as KI or KBr usually used withpalladium catalysts.

The present invention relates to a process for the preparation ofcompound of general formula (I). Preferably the differentcharacteristics of compound of formula (I) may be chosen independentlyfrom each other as being:

-   -   as regards X, X is chlorine;    -   as regards n, n is 1;    -   as regards Y, Y is haloalkyl; more preferably, Y is        trifluoromethyl.

More preferably, the present invention relates to a process for thepreparation of compound of general formula (I) in which:

-   -   X is chlorine;    -   n is 1;    -   Y is trifluoromethyl.

The process of the present invention is particularly suitable for thepreparation of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine.

The process according to the present invention is carried out at atemperature of from 30° C. to 70° C., preferably at a temperature offrom 35 to 50° C.

The process according to the present invention is carried out under apressure of hydrogen of from 1 to 50 bar, preferably under a pressure offrom 2 to 30 bar, more preferably under a pressure of from 10 to 20 bar.

The process according to the present invention is carried out in thepresence of Ni—Ra. Ni—Ra is preferably introduced in a weight ratio offrom 1 to 20% with respect to 2-cyanopyridine derivative of generalformula (II).

The process according to the present invention is particularly suitablefor the preparation of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine,by hydrogenation of 3-chloro-2-cyano-5-trifluoromethylpyridine in aceticacid using Ni—Ra introduced in a weight ratio of from 1 to 20% withrespect to 2-cyanopyridine derivative of general formula (II), at atemperature of from 40 to 50° C., under a hydrogen pressure of from 15to 20 bar.

The catalyst may be recycled according to methods well known by the manordinary skilled in the art. Particularly, the catalyst may be easilyrecycled by filtration.

The process according to the present invention will now be illustratedwith reference to the following example.

Example of the Preparation of2-aminomethyl-3-chloro-5-trifluoromethylpyridine

400 g of acetic acid and 6 g of Ni—Ra (previously washed with wateruntil washings were at a pH of 7) were loaded in a 1 L stainless steelreactor. The reactor was purged with nitrogen and then hydrogen. Heatingwas applied to the reactor to raise the temperature up to 40° C. and thereactor pressure was raised to 18 bar with hydrogen.

120 g of 3-chloro-2-cyano-5-trifluoromethylpyridine (0.571 mol) wereadded by pump over 2 hours. The reaction was exothermic and temperatureraised to 45° C. Hydrogen consumption was monitored. After 2 hours, nomore hydrogen was consumed and the reaction was complete. The mixturewas cooled down to 20° C. and then vented off and purged with nitrogen.

The catalyst was filtered. The solution of2-aminomethyl-3-chloro-5-trifluoromethylpyridine acetic acid salt wasassayed by liquid chromatography. 0.558 moles of2-aminomethyl-3-chloro-5-trifluoromethylpyridine was formed and a 97%yield of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine over3-chloro-2-cyano-5-trifluoromethylpyridine was obtained. A yield of only0.05% yield of the dechlorinated analogue was obtained.

1. A process for the preparation of a 2-aminomethylpyridine derivativeof general formula (I)

wherein n represents 0, 1, 2 or 3, X is a halogen atom, each Y, whichmay be the same or different, is selected from the group consisting of ahalogen atom, halogenoalkyl, alkoxycarbonyl, and alkylsulphonyl, or asalt thereof; comprising hydrogenating a 2-cyanopyridine derivative ofgeneral formula (II):

in which n, X, and Y are as described above, in acetic acid using Raneynickel, at a temperature of from 30° C. to 70° C., under a hydrogenpressure of from 10 to 20 bar.
 2. A process for the preparation of2-aminomethyl-3-chloro-5-trifluoromethylpyridine comprisinghydrogenating 3-chloro-2-cyano-5-trifluoromethylpyridine in acetic acidusing Raney nickel introduced in a weight ratio of from 1 to 20% withrespect to the 3-chloro-2-cyano-5-trifluoromethylpyridine, at atemperature of from 40 to 50° C., under a hydrogen pressure of from 15to 20 bar.
 3. The process of claim 1 wherein X is chlorine.
 4. Theprocess of claim 1 wherein n is
 1. 5. The process of claim 1 wherein Yis haloalkyl.
 6. The process of claim 5 wherein Y is trifluoromethyl. 7.The process of claim 1 wherein X is chlorine, n is 1 and Y istrifluoromethyl.
 8. The process of claim 7 wherein the compound ofgeneral formula (I) is 2-aminomethyl-3-chloro-5-trifluoromethylpyridine.9. The process of claim 1 wherein the temperature is is in the range offrom 35 to 50° C.
 10. The process of claim 1 wherein the Raney nickel isintroduced in a weight ratio of from 1 to 20% with respect to compoundof general formula (II).
 11. The process of claim 8 wherein thetemperature is chosen from 35 to 50° C. and the pressure of hydrogen ischosen from 10 to 20 bar and Raney nickel is introduced in a weightratio of from 1 to 20% with respect to the compound of general formula(II).